Azathioprine for IBD :

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Azathioprine for IBD Better the devil you know
Jeremy D. Sanderson
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Azathioprine for inducing remission in active IBD
425 patients (209 AZA/6-MP, 216
placebo) End-points steroid sparing effect,
clinical response Overall response
Aza/6-MP 54 (CI 47-61) placebo 33 (CI
27-40) Pooled OR 2.36 (CI 1.57 3.53) Time
to respond Present 1980 av. 3.1 months OR 1.54
if lt17 weeks Rx OR 2.51 if gt17 weeks
Rx Steroid sparing Aza/6-MP 65 (CI
56-74) placebo 36 (CI 27-45) Pooled
OR 3.86 (CI 2.14 6.96)
Sandborn et al, Cochrane Library, Issue 4, 2000
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Background
Azathioprine effective in 70 patients with
IBD 30 failure due to Intolerance 15 No
response 15 Intolerance Bone marrow
suppression Nausea Myalgia, flu-like
symptoms Pancreatitis Hepatotoxicity Othe
r Azathioprine failures MTX, anti-TNFa Surg
ery
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Azathioprine
Xanthine oxidase
TPMT
Thiouric acid
6-Mercaptopurine
6-Me MP
HGPRT
6-thioinosine nucleotide
IMPDH
6-thioguanine nucleotides
-
-
-
Immunosppression
Clinical benefit
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High (Normal)
Intermediate
Very High
Low
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TPMT (thiopurine methyl transferase)
allelic polymorphism
High TPMT 89
Intermediate TPMT 11
Low TPMT 1/300
?very high TPMT
Severe Bone Marrow Suppression !!
High risk of marrow suppression
Low risk
Low risk ? poor responders
-

clinical response
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AZA treatment ?
Homozygous deficient
Consider 2.5 5mg AZA ? Thioguanine Alternative
Rx
Check TPMT Enzyme / genotype
Heterozygous deficient
Normal
Very high
Initiate at 100mg Build to 2mg/kg
Initiate at 25mg Build to 1mg/kg
Initiate at 100mg Build to 2.5 3mg/kg
Reduce dose Switch to 6-MP
Nausea
Tolerant
Intolerant
Flu-like illness Pancreatitis Hepatitis
Alternative Rx ? Thioguanine
Repeat TPMT 6mo 1yr.
Marrow suppression
Reduce dose Check for drugs, 5-nucleotidase
def Parvovirus infection
Induced
No change
Increase AZA
Continue
Non-response...
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Bargain
Azathioprine .. still the best and getting
better
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IBD medical therapy
the Bridge approach
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Crohns disease the Bridge approach
Azathioprine
Antibiotics Nutritional Rx Steroids Methotrexate A
nti-TNFa
Mycophenolate ??
Methotrexate
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Conclusions
Many new and potentially exciting therapies
for refractory IBD
But before you use them ..
Make sure you get the best out of
existing approaches